DRUG RECORD

FLUOXETINE

Introduction

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used as an antidepressant. Fluoxetine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

Background

Fluoxetine (floo ox' e teen) is an antidepressant which was one of the first of the class of selective serotonin reuptake inhibitors (SSRIs) introduced into clinical use. By blocking the reuptake of serotonin in CNS synaptic clefts, SSRIs increase serotonin levels in the brain which is associated with their antidepressant effect. Fluoxetine was approved for use in the United States in 1987 and it has become one of the most widely used antidepressant medications, more than 20 million prescriptions being written yearly. Current indications include major depressive disorders, panic and obsessive compulsive disorders, bulemia nervosa and bipolar illness in combination with other agents. Fluoxetine is available as tablets and capsules of 10, 20 and 40 mg and in an oral solution of 20 mg/5 mL, in multiple generic forms and under the brand names of Prozac and Sarafem. Fixed combinations of fluoxetine with olanzapine (Symbyax and generic forms) are also available. A long acting formulation of 90 mg of fluoxetine has been developed for once weekly dosing (Prozac weekly). The recommended dosage of standard formulations of fluoxetine in adults is 20 mg once daily, increasing to 40 mg daily if necessary and not exceeding 80 mg daily. Common side effects are drowsiness, dyspepsia, nausea, headache, increased sweating, increased appetite, weight gain and sexual dysfunction.

Hepatotoxicity

Liver test abnormalities have been reported to occur rarely in patients on fluoxetine (less than 1%), and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on fluoxetine. The onset of injury is usually within 2 to 12 weeks and the pattern of serum enzyme elevations is usually hepatocellular, but convincing cases of mixed and cholestatic injury have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

Mechanism of Injury

The mechanism by which fluoxetine causes liver injury is not known. Fluoxetine is extensively metabolized by the liver, mainly via the cytochrome P450 system, and hepatotoxicity may be mediated by toxic intermediates of their metabolism.

Outcome and Management

The serum aminotransferase elevations that occur on fluoxetine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. Rare instances of acute liver failure and chronic hepatitis have been attributed to fluoxetine therapy. Persons with intolerance to fluoxetine may have similar reactions to other SSRIs and careful monitoring is warranted if other such agents are used.

A 49 year old man with depression developed jaundice five months after starting fluoxetine (20 mg daily), sulpiride (100 mg daily) and diazepam (10 mg daily). He had no history of liver disease or jaundice, but drank an estimated 38 grams of alcohol (~3-4 drinks) daily. He was taking no other medications. Physical examination showed jaundice but no fever or rash. Laboratory testing showed bilirubin of 13.6 mg/dL (direct 11.6 mg/dL), modest elevations in serum aminotransferase levels (ALT 88 U/L; AST 188 U/L), but marked increases in alkaline phosphatase (682 U/L) and gamma glutamyl transpeptidase levels (1,560 U/L) (Table). Tests for hepatitis A, B and C were negative as were autoantibodies. Abdominal ultrasound, CT scans and ERCP showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis, mild portal inflammation, and isolated single hepatocyte necrosis. Fluoxetine was stopped, and he began to improve quickly. In follow up 40 days later, laboratory tests were normal.

Key Points

Medication:

Fluoxetine

Pattern:

Cholestatic (R=0.9)

Severity:

3+ (jaundice, hospitalization)

Latency:

5 months

Recovery:

1-2 months

Other medications:

Sulpiride, diazepam

Laboratory Values

Time After Starting

Time After Stopping

ALT (U/L)

Alk P (U/L)

Bilirubin (mg/dL)

Other

Fluoxetine taken for 5 months

5 months

0

88

682

13.6

Hospitalized

5.3 months

10 days

54

329

3.3

Liver biopsy

6 months

6 weeks

26

297

0.7

Normal Values

<40

<280

<1.2

Comment

The selective serotonin reuptake inhibitors (SSRIs) are some of the most commonly used prescription medications worldwide, yet reports of clinically apparent hepatic injury during their use are rare. Typically, the latency to onset is 1 to 6 months and the pattern of injury is either an acute hepatocellular or cholestatic hepatitis that is self-limited and rapidly reversed upon withdrawal of the agent. Sulpiride is substituted benzamide, an antipsychotic medication used in Europe but not available in the United States; it has not been clearly implicated in cases of drug induced liver injury. When patients develop clinically apparent liver injury from an SSRI, it is not clear whether another member of this group can be substituted. A structurally unrelated substitute along with careful monitoring is perhaps prudent if antidepressant therapy is considered necessary.

Product labeling at DailyMed, National Library of Medicine, NIH

References updated: 26 March 2014

Zimmerman HJ. Antidepressants. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8. (Expert review of hepatotoxicity published in 1999; mentions that there have been at least 6 reports of acute, symptomatic hepatic injury and one case of chronic hepatitis attributed to fluoxetine).

Cooper GL. The safety of fluoxetine – an update. Br J Psychiatry 1988; 153: 77-86. PubMed Citation(Pooled data on 2938 patients on fluoxetine, 599 on tricyclics and 799 on placebo and postmarketing data on over 7500 fluoxetine treated patients; AST values above 100 U/L occurred in 0.5% of patients on fluoxetine, but there were no cases of clinically apparent liver injury).

Lam KS, Blanchi A, Chavaillon JM. [Hepatitis probably secondary to the massive ingestion of fluvoxamine]. Gastroenterol Clin Biol 1988; 12: 398-9. PubMed Citation(63 year old woman took an overdose of fluvoxamine [~1500 mg] and within 24 hours had elevations in ALT [1059 U/L], Alk P [668 U/L] and bilirubin [1.4 mg/dL], which remained high for more than a month).

Grohmann R, Rüther E, Engel RR, Hippius H. Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug safety program: methods and first results for tricyclic antidepressants and SSRI. Pharmacopsychiatry 1999; 32: 21-8. PubMed Citation(Analysis of reporting of adverse events among inpatients in 29 German hospitals between 1993 to 1997; 896 severe adverse events were reported among 48,564 patients [1.8%], both total and hepatic events were more common with tricyclics than SSRIs).

Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. PubMed Citation(Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 3 were attributed to paroxetine and 3 to fluoxetine with a relative risk of injury to rate of use in the population of 3.0 and 1.8, respectively).

Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence,
presentation and outcomes in patients with drug-induced liver iInjury in the
general population of Iceland. Gastroenterology 2013; 144: 1419-25.PubMed Citation(In a population
based study of drug induced liver injury from Iceland, 96 cases were identified
over a 2-year period, but none were attributed to an SSRI despite the fact that 5 SSRIs ranked among the top 30 most prescribed drugs in Iceland).